In the past funding period we have significantly advanced our understanding on the virus/host interaction and receptors for human noroviruses (NVs): we have 1) described eight receptor binding patterns of NVs with human histo-blood group antigen (HBGAs) receptors, 2) mapped the receptor binding domain on the viral capsids by genetic and mutagenesis approaches, 3) elucidated the receptor binding interfaces by cryo-EM and crystallography, 4) discovered a unique subviral particle, the P particle, of NVs, which have greatly facilitated our ability to characterize NV-host interaction, and 5) obtained evidence of HBGA as an important factor in NV evolution based on genetic analysis of the receptor binding interfaces of NVs. These advancements strongly suggest that the HBGAs play an important role in host interaction and tropism of NVs. In addition, our and others'studies suggested that, like many non-enveloped viral pathogens, NVs may need a two-step process to enter into host cells to initiate infection (viral replication). The binding to the HBGAs is the first step that allows virions to attach to the host cells. In the second step, another receptor or co-receptor facilitates the attached virions to penetrate or enter into host cells. This two-step process has been proven for the feline calicivirus (FCV) that uses the sialic acid for attachment and fJAM- 1 for penetration. In this application we will characterize the two-step process of NVs by performing three lines of studies: 1) to search and characterize a functional receptor(s) or co- receptor(s) that involve in the penetration or entry of NVs into host cells, 2) to define the roles of HBGAs in NV binding/attachment to cell surfaces and tropism to the host, and 3) to develop a platform for screening and rational design of antivirals against NVs by computer- aided drug design (CADD) methods. We will take advantage of the newly developed TV cell culture as a model, follow the footsteps of FCV and use our newly resolved crystal structures of NVs to fulfill the goals. The research team includes experts in molecular virology, bioinformatics, structural biology and drug development and medicinal chemistry and with an outstanding track record in the past. We are confident that we will make a rapid progress in this application.